ABSTRACT Delirium is a common and costly problem, affecting up to half of hospitalized older adults, and resulting in substantial morbidity, cognitive decline, loss of functional independence, and increased mortality. Delirium is particularly problematic in patients with Alzheimer's dementia who have an increased risk for delirium, and in whom delirium accelerates the rate of cognitive decline. However, our understanding of the neurological basis of the risk for and effects of delirium in a given individual remains very limited. This project seeks to address this important knowledge gap by utilizing magnetic resonance imaging (MRI)-guided (neuronavigated) transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) and electromyography (EMG) to evaluate cortical function in patients undergoing elective surgery. In a prospective cohort of 180 patients we will examine whether decreased brain network connectivity and altered mechanisms of cortical plasticity as characterized by TMS-EEG-EMG are associated with the risk of developing post-operative delirium. We will record TMS-evoked potentials (TEP) from dorsolateral prefrontal cortex, inferior parietal lobule, and primary motor cortex, before and after intermittent theta-burst stimulation (iTBS). We hypothesize that baseline EEG spectral power and connectivity, TMS-based measures of cortical reactivity and connectivity, and iTBS measures of cortical plasticity will be decreased in patients who subsequently develop delirium, and that patients with greater abnormalities in EEG features and TMS measures at baseline will have greater delirium severity and greater short-term cognitive decline after an episode of delirium. We will correlate neurophysiologic measures with changes in cognitive performance and subsequent cognitive decline in patients with versus without delirium. We hypothesize that EEG alpha power and connectivity, TMS reactivity, TEP cortical connectivity, and efficacy of the mechanisms of cortical plasticity will show greater decreases in patients with delirium than in those without, and will correlate with the magnitude of cognitive decline. Finally, in patients with a previously observed episode of delirium (in SAGES I) we will compare those with and without a history of delirium, and hypothesize that cortical physiology abnormalities will correlate with long-term cognitive decline after delirium (complicated delirium). Ultimately, our results will define neurophysiologic characteristics that can identify individuals with a vulnerable brain susceptible to delirium and subsequent cognitive decline, will provide novel tools to efficiently assess the effectiveness of interventions to help increase individual cerebral resilience and reduce the risk of delirium, and will guide development of therapeutic interventions to help normalize cerebral dysfunction and minimize long-term cognitive decline after delirium.